Toxic oversight

For years, government regulators and academic researchers have been at an impasse over the safety of bisphenol A, or BPA, a chemical used to make some plastics. Academic researchers have repeatedly found that BPA and other hormone-disrupting chemicals, which can contaminate foods and drinks, may contribute to problems such as early puberty, obesity, diabetes, developmental delays and even cancer.

Yet the Food and Drug Administration (FDA), the agency tasked with protecting public health by ensuring the safety of the nation’s food, insists these chemicals are safe at the levels getting into most Americans’ bodies.

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Now, the first round of results are out from a six-year study meant to clear up confusion over BPA’s potential health harms, and they appear to at least partially support academic researchers’ longstanding concerns that exposure to even small amounts of the chemical can cause adverse changes within the body. But the FDA has so far remained resolute in its stance that BPA is safe for consumers, leading some experts to accuse the agency of ignoring the best available science.

The outcomes of the project, called Consortium Linking Academic and Regulatory Insights on BPA Toxicity, or CLARITY-BPA for short, could have major consequences for the way the FDA assesses the safety of BPA and many other chemicals used in food packaging and processing.

“If this study shows that what we’ve been doing to regulate chemicals for decades is the wrong thing, then we are in a bad place with tens of thousands of other chemicals,” said Laura Vandenberg, an environmental health scientist from the University of Massachusetts-Amherst, who was not involved in CLARITY-BPA.

Concerning new research

At her laboratory at North Carolina State University, Heather Patisaul studies how exposures to hormone-mimicking chemicals such as BPA can shape brain development. She uses rats and mice for her experiments, but there are a lot of similarities in the way that rodent pups and human babies form within the womb, she said.

During the earliest stages of life, for instance, estrogen — a sex hormone — causes certain parts of the fetal brain to wire differently in males and females. Over the past decade, Patisaul has shown several times that BPA changes the way the fetal brain uses estrogen. In utero exposure can lead to earlier puberty for females, altered development of the sex-specific parts of the brain, and an increase in anxiety-related behaviors later in life for both males and females.

Patisaul’s findings are concerning because she detected these changes after feeding her rodents really small amounts of BPA — levels she says are comparable to the low levels of the chemical found in the average American’s body.

North Carolina State University professor Heather Patisaul, seen here with scans of rat brains used in BPA-CLARITY, studies how exposures to hormone-mimicking chemicals such as BPA can shape brain development.

“That we’ve seen this effect over and over again is pretty convincing evidence that the the brain is a particularly sensitive target for BPA and other endocrine disruptors,” said Patisaul. “Regulatory testing does not traditionally look for neural effects before or even after chemicals come to market, so we are likely missing many kinds of potential chemical threats to the developing brain.”

She and other academic researchers are doing cutting-edge research that’s changing the way scientists and the public think about toxic substances and the harm that exposure to them might cause. Much of this research has been funded by the National Institutes of Health (NIH), the nation’s medical research agency.

Patisaul called that research “the fuel of bioscience progress.” NIH-funded scientists explore the basic biology of development and other complex processes needed to understand toxicology, pharmacology and all other fields of medicine, she added.

A growing divide

Despite the quality of cutting-edge academic research like this, the FDA ignores most of these academic studies when assessing the toxicity of potentially dangerous chemicals in food and food packaging.

The reason for that is academics don’t follow federal regulatory guidelines for toxicity testing.

That’s because regulators and academic scientists have a different approach to science that’s necessitated by the kinds of questions each group is trying to answer. Academic science is free-ranging and inquisitive, incentivizing innovation and non-traditional approaches to problem-solving. Regulatory scientists, on the other hand, aren’t necessarily trying to make new discoveries and primarily want to evaluate the safety and efficacy of those advancing technologies.

“Academics go where the data take them, whereas regulatory science is more prescribed,” said Maricel Maffini, an independent chemical safety consultant in Washington, D.C.

The regulatory guidelines that the FDA uses to assess the safety of food additives and other chemicals were devised in the 1970s. At that time, the FDA was on the leading edge of the science, said Maffini. “Today, those guidelines have fallen behind the scientific knowledge.”

The agency hasn’t updated or changed the safety tests included in its regulatory guidelines in more than 40 years. Maffini, Patisaul and others say the tests that form the foundation of the regulatory guidelines may no longer be sufficient to protect human health. They were designed at a time before scientists had uncovered the ability of certain chemicals to tinker with our hormones.

So-called regulatory guideline studies look for extremely obvious changes — did exposure to a certain chemical cause a test animal to spontaneously grow a huge tumor on its liver? Did the rat’s nervous system get so messed up it now can’t stand up when you flip it over on its back? The chemicals used in food packaging aren’t so overtly toxic, especially not at the trace levels most people ingest. But just because these chemicals aren’t severely maiming or killing us upon ingestion doesn’t necessarily mean that they are safe, Vandenberg explained.

Take brain development, for instance. Patisaul said that the regulatory guideline studies don’t do a very good job of picking up on many neurological deficits that could result from such a toxic exposure. That’s because the tests they prescribe look only at brain weight.

Looking for changes in the brain weight of rodents allows scientists to detect serious brain abnormalities such as brain tumors or degenerative diseases that eat holes in the brain. These are good tests for detecting tumors and death, Patisaul said, but they aren’t sensitive enough to pick up on more subtle neurological deficits — things like autism-like or ADHD-like behaviors. It’s not possible to tell whether the behavior of an animal has changed by simply putting the brain on a scale.

It may come as little surprise that the FDA would be slow to act on new science. After all, government agencies are set up to resist hastily-made changes. In theory, this makes them less susceptible to undue influence from politicians, industry and special interest groups. But in this case, academic researchers say adherence to outmoded guidelines means regulators almost always favor industry studies over independent science.

In 2008, for example, the FDA found that BPA posed no risk to human health at the low doses found in food packaging. They relied on two industry-funded studies which found no effect, while discounting more than 100 peer-reviewed academic studies that found evidence of harm, according to a survey in Science magazine. Later, in a 2014 risk assessment, the FDA declared that BPA posed no risk to the developing brain based on a single industry-funded study that found no effect while ignoring 35 other federally-funded studies investigating the effects of BPA on neurodevelopment.

It’s a concrete example of how myopic the regulatory process can be, said Patisaul, who’s own research, showing how BPA may be altering brain development, was excluded from the decision-making process.

Enter the Consortium Linking Academic and Regulatory Insights on BPA Toxicity (CLARITY-BPA), a $30-million federal research program started in 2012.

CLARITY-BPA was designed to be a two-armed study: one arm would test the effects of BPA using the traditional guidelines to look for overt changes in things like body weight, and the other arm would test more subtle endpoints chosen by academic scientists. Both sides agreed to a standardized set of scientific protocols and to share a set of tissues from the same rodents. This would help to create identical conditions between the two prongs of the study and minimize the potential for bias. The National Toxicology Program, an interagency program of the U.S. Department of Health and Human Services, would serve as an impartial referee and at the end would release a final report interpreting the results of the two study arms.

The purpose of CLARITY-BPA is to “study the full range of potential health effects from exposure to BPA and to provide data that can be used for regulatory decisions,” according to the National Toxicology Program.

It was designed to show “whether current safety assessment studies on endocrine-active substances are health protective or whether they need to be modified in some way,” said John Bucher, a National Toxicology Program senior scientist.

Patisaul was one of 14 scientists chosen from colleges and universities across the country to participate. Many had been frustrated at seeing their research discounted by regulators and were eager to participate in the regulatory process through science. Patisaul hoped doing so could help level the playing field between regulators and the academic research community.

“I think we were all pretty enthusiastic about the partnership at the outset, but the success of the project really hinges on whether the FDA acts like an honest broker,” she said.

Communication breakdown

But so far, FDA actions to this point have some in the CLARITY-BPA program worried the agency intends to undercut the collaboration.

In February, the FDA released a statement on the preliminary results of their arm of the study that read: “Our initial review supports our determination that currently authorized uses of BPA continue to be safe for consumers.”

Many groups, including the Endocrine Society, an international medical organization of more than 18,000 clinical endocrinologists and hormone researchers, admonished the FDA’s statement as “premature.”

The FDA’s findings had not yet gone through a rigorous review process, and several of the scientists from the academic CLARITY-BPA arm had yet to publish the findings of their research.

The FDA did not respond to repeated requests for comment on the timing of the press release.

“Let’s put it this way: It’s not a situation that was optimal,” said Bucher of the National Toxicology Program, emphasizing that CLARITY-BPA is “very much a study in progress.”

According to the FDA’s statement, the agency “continues to conclude that BPA is safe for the currently authorized uses in food containers and packaging,” and the new research “builds upon the already extensive data collected in the FDA’s 2014 assessment of the safety of BPA” — the same assessment that overlooked reams of data generated by the academics.

Rats that were fed doses of BPA reflective of the low levels of the chemical found in most Americans’ bodies were slightly more likely to develop mammary tumors, kidney cysts and changes to the cells of the prostate and vagina than rats that received no BPA exposure. The exposed females were also slightly fatter. The findings were detailed in a draft report, made available before a public-comment period in April.

Patisaul highlights portions of rat brains that appear to have been influenced by exposure to BPA.

The Endocrine Society urged caution. “We have significant concerns with the conclusions of the interim Research Report and we strongly urge the FDA and other stakeholders to avoid drawing conclusions regarding the safety of BPA based only on the results presented in the Core Study,” it wrote in a statement.

Independent researchers say the FDA’s preliminary findings are concerning. “The effects do overlap with findings from the academic literature,” said Vandenberg. “These are things that shouldn’t be overlooked.” CLARITY-BPA investigator Ana Soto agreed. Soto, a cancer researcher at Tufts University in Boston, has studied the effects of hormonally-active substances on breast tissue and mammary gland development for more than 30 years.

According to Soto, the FDA’s research showing a significant increase in certain types of mammary tumors in rats given low doses of BPA is “totally consistent” with changes in mammary gland development she has observed in her own studies on BPA over the years.

“Cancer doesn’t appear by miracle. There are subtle yet measurable changes in mammary gland development that precede cancer,” she said.

Soto and others expressed concern over the draft report’s interpretation of data concerning mammary tumors and other worrisome effects in public comments submitted to the National Toxicology Program. Academics, professional organizations and even a foreign health agency criticized the report for appearing to cast doubt on the importance of what the FDA scientists found — which was an increase in mammary tumors in rats exposed to small amounts of BPA.

One way the report did this, said Soto, was by making inappropriate comparisons between the number of mammary tumors in the rats in the lowest BPA-dose group for the CLARITY-BPA study and rats in the non-BPA-exposed group of a previous, unrelated experiment that was performed about a decade earlier. Unlike the non-BPA-exposed rats in the CLARITY-BPA study, the non-BPA-exposed rats in the previous experiment had developed a lot of mammary tumors.

A comparison with an old control group is against common scientific practice, said Soto. A control group should be raised simultaneously and under the same living conditions as the test group, treated identically to the test animals in every other way.

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The regulator’s strategy of using old controls “makes the CLARITY-BPA findings look less likely to be real, because the historical controls were also full of tumors,” said Soto. That is, until you consider that the non-BPA exposed animals in the earlier experiment were housed in polycarbonate cages, a component of which is BPA. It’s possible those rats, too, could inadvertently have been exposed to small amounts of the chemical, says Soto, a detail not included in the draft report.

The FDA countered that such comparisons are not out of the ordinary. “Historical control data are used in these studies, and other studies conducted for regulatory purposes, as one part of the evidence considered,” said FDA spokeswoman Marianna Naum.

Looking ahead

A panel of experts appointed by the National Toxicology Program is now reviewing the FDA’s data to assess its scientific soundness. In August, the academic researchers will publicly release the results from their arm of the study. Then the National Toxicology Program will integrate the two sets of data — a process which could take up to eight months — and present its findings and final recommendations to the FDA.

Ultimately, it’s up to the FDA to decide what to do with those recommendations. They could choose to bring more sensitive tests for toxicity into the regulatory fold. Or they could do nothing at all.

Maffini said the FDA has seldom revoked the approved use of a food additive unless the industry has already abandoned that approved use — for example, the FDA banned BPA in sippy cups and baby bottles in 2012, years after manufacturers had stopped using it in those products. The only time the FDA has revoked the use of a food chemical over safety concerns on its own was in 2015, when the agency banned trans fats after new studies overwhelmingly showed that a diet rich in trans fats could lead to heart disease and death.

Despite the odds, Patisaul sees an opportunity for a larger public discussion about what level of health protections citizens want when it comes to food and other consumer products ahead of the final report.

“If we are comfortable weeding out only the most egregious examples of toxicity, then our current system works fine,” she said. “But if we want to take a more precautionary approach to public health, then we need to change the way we’ve been doing things.”

Lead image: Academic researchers say FDA studies of the effects of BPA and other toxins on brain development measure only the weight of a rat’s brain. This allows scientists to detect serious brain abnormalities, such as tumors, but not more subtle neurological deficits — things like autism-like or ADHD-like behaviors.

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